Intersex Effect of Lamotrigine on the Pharmacokinetic Parameters of CDRI-97/78, a Novel Trioxane Antimalarial Compound, in Rats

Reports regarding drug toxicity and adverse events resulting from coadministration of multiple drugs are increasing at an alarming rate. CDRI-97/78 is an 1,2,4-trioxane antimalarial agent under development which gets metabolized to the in vivo active metabolite 97/63. In order to assess its drug interaction potential, CDRI-97/78 was administered alone and in combination with lamotrigine to male and female rats via the oral route. Quantification of the active metabolite 97/63 in rat plasma was achieved with an LC-MS/MS assay. After oral administration of 97/78, the T-max and C-max values of 97/63 in male rats were 1.75 +/- 0.77 h and 862 +/- 306 ng/mL while female rats showed values for C-max of 622.75 +/- 95.09 ng/mL and for T-max of 7.5 +/- 0.5 h. Coadministration of 97/78 and lamotrigine resulted in decreased T-max and C-max values in both male and female rats (T-max and C-max of 0.77 +/- 0.16 h and 58.58 +/- 6.43 ng/mL in male rats; 1.13 +/- 0.22 h and 62.95 +/- 12.00 ng/mL in female rats, respectively). A statistically significant difference (P<0.05) was observed for the pharmacokinetic parameters of 97/63 after oral administration of 97/78 alone and upon its coadministration with lamotrigine except for the C-max and T-max values in male and for the T-1/2 value in female rats. Statistically, no significant difference for the pharmacokinetic parameters of 97/63 between male and female rats after oral administration of 97/78 alone or in combination with lamotrigine was determined except for T-max The study indicates that coadministration of 97/78, an antimalarial agent, and the antiepileptic lamotrigine may require dose adjustments. Additional clinical drug interaction trials may be required to confirm these findings.